Erythropoietin-derived peptide (HBSP) inhibits caspase-3/GSDME through HMGB1 to regulate pyroptosis and reduce diabetic retinopathy

IF 3.5 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides Pub Date : 2026-10-01 Epub Date: 2026-09-23 DOI:10.1016/j.peptides.2026.171520

Zhiyong Zheng, Qing Liu, Xu Chen, Muzhen Huang, Qing Ye, Min Chen

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引用次数: 0

Abstract

Background

Pyroptosis exerts an important effect on the development of diabetic retinopathy (DR). Helix B surface peptide (HBSP) is derived from erythropoietin (EPO) and has a special role in diabetes. This study explored effect of HBSP on retinal pigment epithelium (RPE) cell pyroptosis in DR and its mechanism.

Methods

ARPE-19 cells were treated with high-glucose (HG) and HBSP. Mice were injected with streptozotocin (STZ) and treated with HBSP. HE staining analyzed pathological changes. EB staining tested integrity of blood-retinal barrier (BRB). RT-qPCR determined HMGB1 mRNA. Western blot detected HMGB1 and pyroptosis-related proteins (NLRP3, caspase-1, GSDMD, caspase-3, GSDME). CCK-8 determined viability of ARPE-19 cells. Changes of cell pyroptosis were observed by transmission electron microscopy.

Results

In STZ-induced diabetic mice, retinal tissue exhibited typical DR lesion, BRB breakdown and increased pyroptosis-related proteins. HG reproduced these events in ARPE-19 cells: viability loss, ultrastructural pyroptotic morphology and activation of both canonical (caspase-1/GSDMD) and non-canonical (caspase-3/GSDME) pyroptotic pathways, with the latter being most pronounced. HBSP dose-dependently rescued retinal architecture, restored BRB integrity in vivo, and normalized HG-lowered cell viability in vitro. HBSP ameliorated HG-triggered pyroptosis, primarily by suppressing caspase-3/GSDME signaling pathway. HBSP alleviated HG-stimulated pyroptosis via downregulating HMGB1. HMGB1 knockdown alleviated HG-triggered pyroptosis, primarily by inhibiting caspase-3/GSDME signaling pathway. In vivo, overexpression of HMGB1 could reverse the therapeutic effect of HBSP and increase pyroptosis.

Conclusion

HBSP suppresses RPE cell pyroptosis by disrupting the HMGB1-caspase-3/GSDME axis, thereby mitigating DR. These findings could illuminate a promising therapeutic avenue for DR.

查看原文本刊更多论文

促红细胞生成素衍生肽（HBSP）通过HMGB1抑制caspase-3/GSDME，调节焦亡，减少糖尿病视网膜病变。

背景：焦亡在糖尿病视网膜病变（DR）的发生发展中起着重要作用。螺旋B表面肽（HBSP）来源于促红细胞生成素（EPO），在糖尿病中具有特殊作用。本研究探讨HBSP对视网膜色素上皮（RPE）细胞焦亡的影响及其机制。方法：采用高糖（HG）和HBSP处理ARPE-19细胞。小鼠注射链脲佐菌素（STZ）和HBSP。HE染色分析病理变化。EB染色检测血视网膜屏障（BRB）的完整性。RT-qPCR检测HMGB1 mRNA。Western blot检测HMGB1和焦热相关蛋白（NLRP3、caspase-1、GSDMD、caspase-3、GSDME）。CCK-8测定ARPE-19细胞活力。透射电镜观察细胞焦亡变化。结果：stz诱导的糖尿病小鼠视网膜组织呈现典型的DR病变，BRB分解，焦热相关蛋白增加。HG在ARPE-19细胞中重现了这些事件：活力丧失、超微结构的焦亡形态以及典型（caspase-1/GSDMD）和非典型（caspase-3/GSDME）焦亡途径的激活，其中后者最为明显。HBSP剂量依赖性地挽救了视网膜结构，恢复了体内BRB的完整性，并在体外使hg降低的细胞活力正常化。HBSP主要通过抑制caspase-3/GSDME信号通路改善hg引发的焦亡。HBSP通过下调HMGB1来减轻hg刺激的焦亡。HMGB1敲低可通过抑制caspase-3/GSDME信号通路减轻hg触发的焦亡。在体内，HMGB1过表达可逆转HBSP的治疗效果，增加焦亡。结论：HBSP通过破坏HMGB1-caspase-3/GSDME轴抑制RPE细胞焦亡，从而减轻DR。这些发现为DR的治疗提供了一条有前景的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Peptides 医学-生化与分子生物学

CiteScore

6.40

自引率

6.70%

发文量

130

审稿时长

28 days

期刊介绍： Peptides is an international journal presenting original contributions on the biochemistry, physiology and pharmacology of biological active peptides, as well as their functions that relate to gastroenterology, endocrinology, and behavioral effects. Peptides emphasizes all aspects of high profile peptide research in mammals and non-mammalian vertebrates. Special consideration can be given to plants and invertebrates. Submission of articles with clinical relevance is particularly encouraged.